Wound packing device with nanotextured surface

ABSTRACT

Embodiments of the invention include wound packing devices and methods of making and using the same. In an embodiment, the invention includes a wound packing device including a plurality of spacing elements comprising a nanotextured surface. The wound packing device can also include a connector connecting the plurality of spacing elements to one another. Other embodiments are also included herein.

This application claims the benefit of U.S. Provisional Application No.62/032,244 filed Aug. 1, 2014, the contents of which are hereinincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to wound packing devices. Morespecifically, the present invention relates to wound packing deviceswith nanotextured surfaces and methods of making and using the same.

BACKGROUND OF THE INVENTION

Wound care is critical to ensure optimal healing of wounds and preventinfection. Wound healing includes sequential phases of inflammation,proliferation, and remodeling. Specific types of wounds require specialcare in order to reach optimal results. By way of example, in thecontext of deep wounds, abscesses and/or infections can occur deep inthe wound bed if the outermost portion of the wound heals over tooquickly.

Materials used to treat wounds include creams, foams, gels, ointments,pads, pastes, powders, or other materials. Some of these may include anantimicrobial that can be released into the wound bed.

SUMMARY OF THE INVENTION

Embodiments of the invention include wound packing devices withnanotextured surfaces and methods of making and using the same. In anembodiment, the invention includes a wound packing device including aplurality of spacing elements having a nanotextured surface. The surfaceof the spacing elements can resist colonization by microorganisms. Thewound packing device can also include a connector connecting theplurality of spacing elements to one another.

In an embodiment, the invention includes a wound packing deviceincluding a plurality of spacing elements, the spacing elementsincluding a nanotextured surface. The wound packing device can alsoinclude a container, the plurality of spacing elements disposed withinthe container.

In an embodiment, the invention includes a method of making a woundpacking device. The method can include forming a plurality of spacingelements, the spacing elements including a nanotextured surface. Themethod can further include mounting the plurality of spacing elements ona connector.

In an embodiment, the invention can include a wound packing kit. The kitcan include a plurality of spacing elements, the spacing elementsincluding a nanotextured surface. The spacing elements can include asurface that resists colonization by microorganisms. The kit can furtherinclude a connector connecting the plurality of spacing elements to oneanother; the connector comprising a fitting to allow for the number ofspacing elements connected to one another by the connector to bemodified by an end user.

In an embodiment, the invention can include a method of treating wounds.The method can include dispensing a wound packing device from a sterilepackage. The wound packing device can include a plurality of spacingelements, the spacing elements including a nanotextured surface, theplurality of spacing elements configured to absorb exudate, and aconnector connecting the plurality of spacing elements to one another.The method can further include inserting the wound packing device into awound bed.

This summary is an overview of some of the teachings of the presentapplication and is not intended to be an exclusive or exhaustivetreatment of the present subject matter. Further details are found inthe detailed description and appended claims. Other aspects will beapparent to persons skilled in the art upon reading and understandingthe following detailed description and viewing the drawings that form apart thereof, each of which is not to be taken in a limiting sense. Thescope of the present invention is defined by the appended claims andtheir legal equivalents.

BRIEF DESCRIPTION OF THE FIGURES

The invention may be more completely understood in connection with thefollowing drawings, in which:

FIG. 1 is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

FIG. 2 is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

FIG. 3 is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

FIG. 3A is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

FIG. 4 is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

FIG. 5 is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

FIG. 6 is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

FIG. 7 is a cross-sectional schematic view of a spacing element inaccordance with various embodiments herein.

FIG. 8 is a cross-sectional schematic view of a spacing element inaccordance with various embodiments herein.

FIG. 9 is a cross-sectional schematic view of a spacing element inaccordance with various embodiments herein.

FIG. 10 is a cross-sectional schematic view of a spacing element inaccordance with various embodiments herein.

FIG. 11 is a cross-sectional schematic view of a spacing element inaccordance with various embodiments herein.

FIG. 12 is a cross-sectional schematic view of a connector in accordancewith various embodiments herein.

FIG. 13 is a cross-sectional schematic view of a connector in accordancewith various embodiments herein.

FIG. 14 is a cross-sectional schematic view of a connector in accordancewith various embodiments herein.

FIG. 15 is a schematic view of a spacing element in accordance withvarious embodiments herein.

FIG. 16 is a schematic view of a spacing element in accordance withvarious embodiments herein.

FIG. 17 is a schematic view of a connector segment and a spacing elementin accordance with various embodiments herein.

FIG. 18 is a schematic view of connector segments and spacing elementsattached to one another in accordance with various embodiments herein.

FIG. 19 is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

FIG. 20 is a schematic view of a plurality of spacing elements disposedwithin a container in accordance with various embodiments of theinvention.

FIG. 21 is a schematic view of a plurality of spacing elements disposedwith a packing material inside of a container in accordance with variousembodiments of the invention.

FIG. 22 is a schematic cross-sectional view of a portion of a device inaccordance with various embodiments herein.

FIG. 23 is a schematic cross-sectional view of a spacing element inaccordance with various embodiments herein.

FIG. 24 is a schematic view of a wound packing device in accordance withvarious embodiments of the invention.

While the invention is susceptible to various modifications andalternative forms, specifics thereof have been shown by way of exampleand drawings, and will be described in detail. It should be understood,however, that the invention is not limited to the particular embodimentsdescribed. On the contrary, the intention is to cover modifications,equivalents, and alternatives falling within the spirit and scope of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the present invention described herein are notintended to be exhaustive or to limit the invention to the precise formsdisclosed in the following detailed description. Rather, the embodimentsare chosen and described so that others skilled in the art canappreciate and understand the principles and practices of the presentinvention.

All publications and patents mentioned herein are hereby incorporated byreference. The publications and patents disclosed herein are providedsolely for their disclosure. Nothing herein is to be construed as anadmission that the inventors are not entitled to antedate anypublication and/or patent, including any publication and/or patent citedherein.

Embodiments of the invention include wound packing devices that areeffective for wound care management. In particular embodiments hereininclude a wound packing device including a nanotextured surface isincluded. As used herein, the term “nanotextured” refers to surfacecharacteristics on a nanometer scale. Surface characteristics caninclude surface topology or roughness, surface charge and/orhydrophobicity. In various embodiments surfaces herein can becharacterized by one or more of surface roughness, surface charge,and/or hydrophobicity that can decrease, inhibit, and/or reduce theability of microorganisms, and in particular bacteria, to adhere to,proliferate on, and/or colonize the surface.

Some embodiments of the invention include beaded wound spacer deviceshaving multiple beads connected by a non-absorbable suture material. Thebeads and/or suture material can have surface nanotexturingcharacteristics to provide advantages as described herein. Exemplarybeaded wound spacer devices include devices of various polymericmaterials that are conducive to etching or scoring to produce ananotextured surface. Without being limiting, examples of such beadedwound spacer devices are described in U.S. Pat. Nos. 8,685,421 and8,697,106 (both to Kloke et al.), the entire content of which are herebyincorporated by reference herein.

The nanotextured surface can take the appearance of etching on thesurface of the medical device, for example in the geometry or structuralfeatures of lines, points, hills, mounds, valleys, slopes and the likeand distances between such geometries and structural features of variousnanometer dimensions such as height and/or width and or length and/ordepth having dimensions in the range from about 1 nanometer to about1000 nanometers. For example nanoscale features within the scope hereininclude those having dimensions between about 10 nanometers to about 900nanometers, about 100 nanometers to about 500 nanometers, about 1nanometer to about 100 nanometers, about 10 nanometers to about 50nanometers, about 1 nanometer to about 10 nanometers, about 1 nanometerto about 5 nanometers, about 10 nanometers to about 100 nanometers, andany ranges in between the above ranges. In some embodiments the lines ofetching are spaced about 600 nm from each other. In other embodimentsthe lines of etching are spaced about 500 nm from each other.

It will be appreciated that nanotextured surfaces can be formed invarious ways. Aspects of nanotextured surface are described in U.S.Publ. Appl. No. 2013/0199539 (to Webster), the content of which isherein incorporated by reference in its entirety. In some embodiments,material can be removed from a surface to leave a nanotextured surface.In other embodiments, material can be deposited onto a surface to createa nanotextured surface. For example, the same or different from thematerial of the substrate surface can be deposited on the surface of thesubstrate using deposition methods including, but not limited to,sputtering, vapor deposition, spraying, and the like. In still otherembodiments, a surface can be stamped, molded, pressed, or otherwiseimprinted or contacted with a surface of another object to create ananotextured surface. Additionally the surface can be chemically etchedor mechanically polished to achieve the desired nanotextured surface.

In yet other process embodiments antimicrobial activity can be impartedto surfaces of natural, biocompatible, biodegradable or syntheticpolymeric materials (for example, but not limited to, chitosan, nylonand polyethylene terephthalate) by production of nanostructuredsurfaces. Exemplary processes include, but are not limited to, plasmatreatment, or plasma treatment followed by treatment with organicfullerene [60] derivatives. The resulting nanostructured surfacesproduced using these processes exhibit increased antimicrobial activitywhen compared with “untreated” control surfaces (Plasma Process. Polym.;New Antimicrobial Materials Based on Polymers with NanostructuredSurface Modified by Organic Fullerene [60] Derivatives; Ellinson et al.,2009, 6, S85-S91).

In various embodiments, a portion of the substrate surface can beremoved by action of a nano-roughing agent. Mechanisms for removingmaterial from a substrate surface include abraiding, degrading,dissolution, etching and the like to produce a nanometer scale surfaceroughness. Particular methods include contacting the surface of thesubstrate with a device that will remove material from the substratesurface, such as by friction or abrasion. Alternatively, a liquid orgaseous material can be applied to the surface of the substrate todegrade, dissolve or etch away material from the surface of thesubstrate to produce a nanometer scale surface roughness. Suchtreatments are referred to as chemical treatments and include liquid orgaseous materials such as acids, bases, lipases, dichloroethylene andxylene and the like. Exemplary nano-roughing agents include one or moreof an acid, a base, an alcohol, a peroxide, isoamyl acetate,dichloromethane, isoamyl acetate with zinc, dichloromethane with zinc,acetic acid, sulfuric acid, nitric acid, perchloric acid, phosphoricacid, hydrochloric acid, chloroform, acetone, ethanol, ammonia, sodiumhydroxide, potassium hydroxide, ammonium hydroxide, ammonium fluoride,hydrofluoric acid, triflic acid, hydrogen peroxide, dichloroethylene,xylene, bacterial lipases, and the like.

In some embodiments, bacterial lipase solutions are used to produce ananometer scale surface roughness on a substrate. According to thisaspect, substrate surfaces are contacted with lipases, for example fromC. cilindracea and R. arrhisus, in a manner to cause enzymaticdegradation of the substrate and nanometer scale features on the surfaceof the substrate. In this manner, a method is provided to create ananometer scale surface roughness having antibacterial properties bycontacting the surface of a substrate with one or more lipases for aperiod of time to allow enzymatic degradation of surface materialsthereby creating nanometer scale features on the surface of thesubstrate. In addition to lipases from C. cilindracea and R. arrhisus,other useful lipases include those from Candida rugosa, Thermusthermophilus, Candida Antarctica, Aspergillus niger, Aspergillus oryzae,Aspergillus sp, Burkholderia sp, Candida utilis, Chromobacteriumviscosum, Mucor javanicus, Penicillium roqueforti, Pseudomonas cepaciaand the like. Other useful lipases and etchants include phospholipases,sphingomyelinases, hepatic lipase, endothelial lipase, lipoproteinlipase, bile salt dependent lipase, pancreatic lipase, lysosomal lipase,hormone-sensitive lipase, gastric lipase, pancreatic lipase relatedprotein 2, pancreatic lipase related protein 1, lingual lipase and thelike.

Referring now to FIG. 1, a schematic view of a wound packing device 100is shown in accordance with various embodiments of the invention. Thewound packing device 100 includes a plurality of spacing elements 102and a connector 104 connecting the plurality of spacing elements 102 toone another. In some embodiments, the wound packing device 100 caninclude from about 4 to 50 spacing elements 102. However, it will beappreciated that other numbers of spacing elements 102 can be includedin other embodiments. The spacing elements 102 can be of various shapesand sizes. In some embodiments, the surface of the spacing elements 102can be substantially smooth. In other embodiments, the surface of thespacing elements 102 can be textured. In some embodiments the surface ofthe spacing elements 102 can include grooves. The spacing elements 102can be sized such that their major dimension is from about 0.5 mm toabout 25 mm. For example, in some embodiments the major diameter of thespacing elements 102 can be from about 0.5 mm to about 2.5 mm. In someembodiments, the surface of the spacing elements 102 is deformable. Inother embodiments, the surface of the spacing elements 102 issubstantially rigid.

The distance 106 between adjacent spacing elements 102 along connector104 in some embodiments can be at least equal to the largest dimensionof the spacing elements 102. In some embodiments, the distance 106between adjacent spacing elements along the connector is at least equalto the diameter of the spacing elements 102. In various embodiments, thedistance 106 between adjacent spacing elements can be greater than 0.5mm, 1.0 mm, 2.0 mm, 3.0 mm, 4.0 mm, 5.0 mm, 10 mm, 15 mm, 20 mm, or insome cases even greater than 25 mm. In yet other embodiments, distances106 between spacing elements 102 can vary along the total length of thewound packing device 100. That is, the connectors 104 can be of varioussizes along a single wound packing device 100. In some embodiments theconnector has a diameter of about 0.1 mm to about 2 mm. In someembodiments the connector has a length of about 5 cm to about 200 cm.

The surface of the spacing elements and/or the connector can beconfigured to resist colonization by microorganisms. In someembodiments, the surface of the spacing elements and/or connector canhave antimicrobial activity. In some embodiments, the surface of thespacing elements and/or connector can include silver ions or graphene.In some embodiments, the surface of the spacing elements and/orconnector can include quaternary amines. In some embodiments, thesurface of the spacing elements and/or connector can include tobramycin.

In certain embodiments, the surface of the spacing elements and/orconnector can include aminoglycoside antibiotics, such as tobramycin,vancomycin, amikacin, gentamicin, kanamycin, neomycin, netilmicin,paromomycin, streptomycin, and apramycin. Other active agents on or inthe surface of the spacing elements can include, for example, variousmodified aryls, and cationic steroidal antibiotics.

Additional suitable active agents on or in the surface include, forexample, antimicrobial peptides such as those taught in U.S. Pat. No.5,714,577 (Antimicrobial peptides); U.S. Pat. No. 5,945,507(Antimicrobial peptides); U.S. Pat. No. 6,835,713 (Virus derivedantimicrobial peptides); and U.S. Pat. No. 6,887,847 (Virus derivedantimicrobial peptides), all of which are incorporated by reference intheir entirety.

In some embodiments the spacing element comprises a polymer selectedfrom the group consisting of polyamide, poly(methyl methacrylate),poly(ether blocked amides) (PEBAX), polyurethane, silicone, nylon,fluoropolymers and combinations thereof. In certain embodiments thespacing elements can be composed of a medical grade polymer.

The plurality of spacing elements 102 can be capable of absorbingexudate from a wound bed. In some embodiments, each spacing element 102can be capable of absorbing an amount of exudate equal to at least theweight of the spacing element 102. In some embodiments, each spacingelement 102 can be capable of absorbing an amount of exudate that isequal to a multiple of the weight of the spacing element 102. Forexample, in some embodiments each spacing element 102 can be capable ofabsorbing an amount of exudate that is equal to at least 2 times, 3times, 4 times, or 5 times the weight of the spacing element 102.

In some embodiments, the plurality of connectors 104 can also be capableof absorbing exudate from a wound bed. In some embodiments, eachconnector 104 can be capable of absorbing an amount of exudate equal toat least the weight of the connector 104. In some embodiments, eachconnector 104 can be capable of absorbing an amount of exudate that isequal to a multiple of the weight of the connector 104. For example, insome embodiments each connector 104 can be capable of absorbing anamount of exudate that is equal to at least 2 times, 3 times, 4 times,or 5 times the weight of the connector 104.

The connector 104 can be flexible. For example, the connector 104 canbend freely in some embodiments so that the wound packing device 100 canassume a bunched or compacted configuration. The wound packing device100 is sufficiently flexible to be bent into a U-shape. Referring now toFIG. 2, a schematic view of the wound packing device 100 is shown withthe connector 104 bent in several places such that the wound packingdevice is curved and the spacing elements 102 are no longer in astraight line. In some embodiments the spacing elements 102 cannot be inthe same plane due to the orientation of the bent connectors 104.

In some embodiments, the wound packing device can include a structuralfeature in order to secure the wound packing device to something else,secure an end of the wound packing device back onto itself or secure thewound packing device to another wound packing device. By way of example,an end of the wound packing device can include a loop of material thatcan be used to attach the wound packing device to something else,another wound packing device or back onto itself. Referring now to FIG.3, a schematic view of a wound packing device 300 is shown in accordancewith various embodiments of the invention. The wound packing device 300includes a plurality of spacing elements 302 and a connector 304. Thewound packing device 300 also includes a loop 308 of material which canbe used to affix the end of the wounding packing device 300 to somethingelse. By way of example, a user can pass a suture through the loop 308in order to secure the wound packing device 300 to something else. Forexample, suture material can be passed through loop 308 to secure thewound packing device 300 for easy removal from a wound. Alternatively,the loop 308 can be passed over the other end of the wound packingdevice so that the two opposite ends of the wound packing device 300 areheld adjacent to one another.

In yet other embodiments a first wound packing device can be attached toa second wound packing device to extend the length of the wound packingdevice. The attachment can be achieved using a spacing element couplingdevice. Referring now to FIG. 3A, a schematic view of a wound packingdevice 350 is shown in accordance with various embodiments of theinvention. The wound packing device 350 includes spacing elements 302and connectors 304. The wound packing device 350 includes a spacingelement coupling device 352. By way of example, one end of the spacingelement coupling device 352 can be appropriately sized to slip overconnector 304 and retain the spacing element 302 on one end of a firstwound packing device and the other unoccupied end of the spacing elementcoupling device 352 can slip over the spacing element 302 of a secondwound packing device, resulting in an extended wound packing device 350.The spacing element coupling device 352 can be similar in function tometal light pull chain extenders used to extend light pull chains onhousehold light pull switches.

In some embodiments, the wound packing device can include a reservoir toretain wound exudate. In some embodiments, the reservoir is an externalstructure separate from other components of the wound packing device. Inother embodiments, the reservoir is a structure disposed within thespacing elements or the connector. Referring now to FIG. 4, a schematicview of a wound packing device 400 is shown in accordance with variousembodiments of the invention. The wound packing device 400 includes aplurality of spacing elements 402 and a connector 404. The wound packingdevice 400 also includes a reservoir 410. The reservoir 410 can definean interior volume that can retain exudate material. By way of example,in some embodiments the connector 404 can include a lumen or channelthat can be in fluid communication with the reservoir 410, and exudatecan pass through the connector 404 into the reservoir 410.

The spacing elements can be disposed along the connector in series withone another. In some embodiments, the spacing elements can be disposedalong the connector such that one or more spacing elements are disposedin parallel with one or more other spacing elements. The connector canbe one continuous piece or it can include multiple segments or branches.Referring now to FIG. 5, a schematic view of a wound packing device inaccordance with various embodiments of the invention is shown. The woundpacking device 500 can include a plurality of spacing elements 502 andconnectors 504. The connector 504 can include a first branch 512, asecond branch 514, and a third branch 516, that intersect one another ata point 518 on the connector 504.

Wound packing devices herein can include one or more fittings tofacilitate attachment and/or removal of segments that include spacingelements so that the total amount of spacing elements or the volume ofspacing elements can be easily adjusted. Referring now to FIG. 6, awound packing device 600 is shown in accordance with various embodimentsof the invention. The wound packing device 600 can include a pluralityof spacing elements 602 and a connector 604. The connector 604 caninclude a first branch 612, a second branch 614, and a third branch 616.The wound packing device 600 can include fittings 620. Manipulation ofthe fittings 620 can allow the branches to be easily removed, orreattached after being removed. The fittings 620 can take on variousforms. In some embodiments the fittings 620 can include a pair ofthreaded elements that fit together. In some embodiments, the fittings620 can include a compression tube fitting (e.g. SWAGELOK fitting), aluer taper fitting, threaded fittings or the like. Other fittingsinclude couplers, 3-way joints (e.g. “T's), 4-way joints (e.g. crosses)and end caps

Referring now to FIG. 7, a cross-sectional schematic view of a spacingelement 700 is shown in accordance with various embodiments herein. Thespacing element 700 can include a core portion 702 of material that canbe effective to absorb exudate. In some embodiments, the spacing element700 is swellable. In some embodiments, the spacing element 700 can becomprised of a porous material for the core portion 702. In someembodiments, the spacing element 700 includes a fluid sequesteringmaterial. The spacing element 700 can define a central channel or lumen704. The connector (not shown in this view) can pass through the lumen704.

The terms “absorbent” or “absorbing” materials as used herein includesmaterials that are capable of adsorbent, adsorbing, retention orretaining of a fluid. Materials of the core portion can includehydrophilic absorbent polymers such as polyacrylic acid,polyacrylamides, polysaccharides (e.g. alginates), terpolymers (forexample copolymers of lactide, glycolide and caprolactone), hydrogels,PEG, PVA, poly(vinyl pyrrolidone) (PVP), poly(hydroxyethylmethacrylate),hyaluronic acid and the like. In some embodiments, the hydrophilicabsorbent polymers may be crosslinked. In some embodiments, the coreportion can include a polyurethane foam. In other embodiments, the coreportion can include hygroscopic agents that promote absorption of water.

In some embodiments, the surface of the spacing elements can bechemically modified in order to change the characteristics of thesurface of the spacing elements. By way of example, in some embodiments,a modifying compound can be covalently bonded to the surface of thespacing elements. It will be appreciated that there are many differenttechniques through which a modifying compound could be covalently bondedto the surface of the spacing elements. One approach can be to use acompound with a thermoreactive group which can covalently bond to thesurface after being activated by application of heat. Another exemplaryapproach can be to use a compound with a photoreactive group which cancovalently bond to the surface after being activated.

Photoreactive groups respond to specific applied external stimuli toundergo active specie generation with resultant covalent bonding to anadjacent chemical surface. For example, in an embodiment, aphotoreactive group can be activated and can abstract a hydrogen atomfrom an alkyl group. A covalent bond can then form between the compoundwith the photoreactive group and the compound with the C—H bond.Suitable photoreactive groups are described in U.S. Pat. Nos. 5,002,582;5,637,460; 5,714,360; and 6,077,698, the disclosures of which areincorporated herein by reference. Further examples of such agents aredescribed in U.S. Publ. Pat. App. No. 2012/0046384, the content of whichis herein incorporated by reference. One example of such a modificationwould be to provide the surface with lubricious characteristics. Thiscan be achieved by modifying the surface of the spacing elements to havehighly hydrophilic properties, such as that provided by PVP orpolyacrylamide. As such, a photo-PVP compound (a compound including aphotoreactive group and PVP) or a photo-polyacrylamide (a compoundincluding a photoreactive group and polyacrylamide) could be used tomodify the surface of the spacing element. Methods for the preparationof photo-PVP are described in U.S. Pat. No. 5,414,075, the content ofwhich is herein incorporated by reference. Methods for the preparationof photo-polyacrylamide are described in U.S. Pat. No. 6,007,833, thecontent of which is herein incorporated by reference.

Exemplary photoreactive groups that can be pendent from the coatings,materials, or surfaces of the wound packing device, include thosedescribed in U.S. Pat. No. 5,414,075 and in U.S. patent application Ser.No. 13/490,994 (to Swan et al. and filed Jun. 7, 2012), the disclosuresof which is incorporated herein by reference.

This material includes a chemical backbone having attached to it one ormore first latent reactive groups and one or more second latent reactivegroups, each of the first and second latent reactive groups beingattached to the backbone in such a manner that, upon activation of thelatent reactive groups in the presence of a support surface, a) thefirst latent reactive groups are capable of covalently bonding to thesupport surface, and b) upon bonding of the first latent reactive groupsto the surface, the second latent reactive groups are; i) restrictedfrom reacting with either a spacer or the support surface, ii) capableof reverting to their inactive state, and iii) upon reverting to theirinactive state, are thereafter capable of being reactivated in order tolater bind a target molecule, thereby attaching the target molecule tothe surface.

In a particularly preferred embodiment, the chemical backbone of such amultifunctional reagent is a single tetrahedral carbon atom. Attached tothe central carbon, in this embodiment, are four identical latentreactive groups, in the form of photoreactive groups, each attached viaidentical spacer chains. Upon exposure to a suitable light source, eachof the latent reactive groups are subject to activation.

By virtue of conformational and/or steric constraints that the reagentimposes on itself (hence “restrained”), both by the tetrahedral natureof the central carbon, as well as the physical-chemical nature of thespacer chains themselves (e.g., their length, reactivity, andflexibility), the reagent is restricted, in that a maximum of three ofthe four activated latent reactive groups on any given preferred reagentmolecule are able to attach to the support surface. The remainingunreacted group(s) are thus able to revert to their inactive state. In asubsequent step, the unreacted group(s) can be reactivated in thepresence of a target molecule, in order to covalently bond the targetmolecule to the surface.

The reagent of the present invention involves a chemical backbone havingattached to it one or more first latent reactive groups capable ofattaching to a surface, and one or more second latent reactive groupscapable of attaching to a target molecule intended for immobilization.Chemically, the first and second latent reactive groups, and respectivespacers, can be the same or different.

In situations in which all latent reactive groups and spacers arechemically, or at least functionally, the same, the distinction betweenfirst and second latent reactive groups may actually be accomplished atthe time of the first activation step, i.e., those groups that areactivated and attach to the surface will be considered “first” latentreactive groups, and those that remain unreacted (whether or not theyhave been activated) will be considered “second” latent reactive groups.

The first and second latent reactive groups are preferably attached tothe backbone by spacer chains in such a manner that, upon activation ofthe latent reactive groups in the presence of a support surface, thefirst latent reactive groups are capable of covalently bonding to thesurface. The second latent reactive groups are thereby conformationallyrestricted, thus preventing reaction with either their spacers, otherrestricted reagents of the same type, or the support surface. Inaddition, after the first activation step and removal of the activatingstimulus (e.g., illumination source), the second latent reactive groupsare capable of reverting to their inactive state and can thereafter beactivated (or reactivated, as the case may be) to covalently bond atarget molecule.

The following diagram depicts the concept of the preferred tetrahedralcore structure, as exemplified by the empirical formula X(Y)₄(Z)₄, shownbelow as Formula I:

In Formula I:

-   -   X=the chemical backbone;    -   Y₁, Y₂, Y₃, Y₄=optional spacers; and    -   Z₁, Z₂, Z₃, Z₄=latent reactive groups.

In an embodiment, the invention provides a core molecule containing fourdimethyleneoxy groups bonded as spacers to a central tetrahedral carbonatom, the carbon atom serving in this instance as the chemical backbone.The backbone, spacers, and latent reactive groups are described herein,for the sake of simplicity, as being distinct portions of the reagent ofthe present invention. In the chemical synthesis of a reagent however,these portions will rarely be provided as three independent precursors.Instead, and most often, the portion referred to herein as the spacerwill be formed as the result of the reaction between two molecules, onethat contains the core molecule and another that contains the latentreactive group.

By virtue of the physical and chemical properties of the photoreactivegroups and the methylene group spacers, together with the conformationalrestrictions provided by the tetrahedral carbon backbone, the reagent isable to attach up to three of its photoreactive groups to a surface uponphotoactivation. Being conformationally restricted, and thus unable tointeract with the support surface or the spacers, any remainingphotoreactive group(s) are able to return to their inactive states uponremoval of fight, once again being capable of activation by subsequentillumination.

In addition to reagents of the particularly preferred embodiment,containing a central carbon atom, reagents of the present invention canbe prepared having any suitable chemical (e.g., organic and/orinorganic) backbone structure, including those that employ a singleatom, such as silicon, nitrogen, phosphorus, and any other atom withfour or more bonds nonplanar with respect to one another.

Also, molecules having conformationally restricted ring structures (suchas inositol, i.e., hexahydroxy cyclohexane) can be derivatized withlatent reactive groups in a manner analogous to that described hereinfor pentaerythritol, to provide latent reactive groups in both axial andequatorial positions. Other polyhydroxylated compounds such as mono- anddi-saccharides, and cyclodextrins, are suitable as well, in that theyoffer alternative opportunities to create other multisubstitutedreagents having varying placements and densities of latent reactivegroups.

Contact with a support surface and activation of the latent reactivegroups will result in covalent bond formation through at least onelatent reactive group, with at least one other latent reactive groupbeing conformationally restricted and thus unable to react at thesurface.

Spacers useful in the reagent of the present invention can be bonded tothe tetrahedral atom and can be of any suitable length and structure. A“spacer”, as used herein, refers to that region of a reagent between alatent reactive group and a chemical backbone. The use of spacers isoptional, and would not be necessary, for instance, for such compoundsas acylated derivatives of tetraphenylmethane having the structure shownbelow as Formula II:

A “latent reactive group”, as used herein, refers to a chemical groupthat responds to an applied external energy source in order to undergoactive specie generation, resulting in covalent bonding to an adjacentchemical structure (e.g., an abstractable hydrogen). Preferred groupsare sufficiently stable to be stored under conditions in which theyretain such properties. See, e.g., U.S. Pat. No. 5,002,582, thedisclosure of which is incorporated herein by reference. Latent reactivegroups can be chosen that are responsive to various portions of theelectromagnetic spectrum, with those responsive to ultraviolet andvisible portions of the spectrum (referred to herein as “photoreactive”)being particularly preferred.

Photoreactive aryl ketones such as acetophenone and benzophenone, ortheir derivatives, are preferred, since these functional groups,typically, are readily capable of undergoing theactivation/inactivation/reactivation cycle described herein.Benzophenone is a particularly preferred photoreactive group, since itis capable of photochemical excitation with the initial formation of anexcited singlet state that undergoes intersystem crossing to the tripletstate. The excited triplet state can insert into carbon-hydrogen bondsby abstraction of a hydrogen atom (from a support surface, for example),thus creating a radical pair. Subsequent collapse of the radical pairleads to formation of a new carbon-carbon bond. If a reactive bond(e.g., carbon-hydrogen) is not available for bonding, the ultravioletlight-induced excitation of the benzophenone group is reversible and themolecule returns to ground state energy level upon removal of the energysource. Hence, photoreactive aryl ketones are suitable.

A linking agent suitable for use in the present material is described inU.S. Pat. No. 5,714,360, the disclosure of which is incorporated hereinby reference.

A chemical linking agent including a di- or higher functionalphotoactivatable charged compound can be employed. This linking agentprovides at least one group that is charged under the conditions of usein order to provide improved water solubility. The agent furtherprovides two or more photoactivatable groups in order to allow the agentto be used as a cross-linking agent in aqueous systems. In anembodiment, the charge is provided by the inclusion of one or morequaternary ammonium radicals, and the photoreactive groups are providedby two or more radicals of an aryl ketone such as benzophenone.

In a preferred embodiment, the invention provides a linking agent of thegeneral formula: X—Y—X; wherein each X, independently, is a radicalcontaining a photoreactive group and Y is a radical containing, interalia, one or more charged groups. In such an embodiment, the numberand/or type of charged group(s) is sufficient to provide the moleculewith sufficient aqueous solubility to allow the agent to be used (i.e.,applied to a surface and activated) in a solvent system having water asa major component.

In an embodiment, Y contains one or more nitrogen-containing (e.g.,quaternary ammonium) groups. For example, Y contains a linear orheterocyclic radical selected from the group consisting of:

wherein each R¹ independently is a radical containing an alkylene,oxyalkylene, cycloalkylene, arylene, or aralkylene group, each R²independently is a radical containing an alkyl, oxyalkyl, cycloalkyl,aryl, or aralkyl group, and each R³ independently is either anon-bonding pair of electrons, a hydrogen atom, or a radical of the samedefinition as R², in which the R¹, R² and R³ groups can containnoninterfering heteroatoms such as O, N, S, P and the like, and/ornoninterfering substituents such as halo (e.g., Cl) and the like.

In an embodiment, one or more R² radicals contains an aralkyl group inthe form of a photoactivatable aryl ketone. These groups, in addition tothe two photoactivatable groups provided by the above-defined X groups,can be used to provide the “triphoto”, “tetraphoto” and higher orderphotoactivatable groups described herein. The use of three or more totalphotoreactive groups provides the linking agent with further ability tocross-link the agent to a target molecule and/or to a surface.

In yet another preferred embodiment, the R² and R³ groups of the abovelinear radicals can, in effect, be fused (e.g., an R² and an R³ on asingle N atom, or a suitable combination of R²/R³ groups on adjacent Natoms) in order to form heterocyclic structures other than thoseexemplified above. The specific choice and relationship between R groupsin a linking agent of the present invention is not critical, so long asthe linking agent provides two or more photoactivatable groups andretains sufficient water solubility for its intended use.

Linking Agent

A water-soluble, linking agent suitable for use as the present device isdescribed in U.S. patent application Ser. No. 13/074,537 (Kurdyumov etal.; filed Mar. 29, 2011), the disclosure of which is incorporatedherein by reference.

The linking agent can have the formula Photo¹-LG-Photo², wherein Photo¹and Photo², independently, represent at least one photoreactive groupand LG represents a linking group. In one embodiment, one or morephotoreactive groups include an aryl ketone. In a more particularembodiment, one or more photoreactive groups include benzophenone.

In one embodiment, the linking group includes one or more silicon atomsor one or more phosphorus atoms, wherein each photoreactive group isindependently bonded to the linking group by a covalent linkage thatincludes at least one heteroatom. In one embodiment, at least oneheteroatom is selected from oxygen, nitrogen, selenium, sulfur, or acombination thereof. In one embodiment, at least one photoreactivegroup, heteroatom and linking group form an ether or an amine.

In a more particular embodiment, the linking group includes one siliconatom covalently bonded to at least two photoreactive groups. In anotherembodiment, the linking group includes at least two silicon atoms. Inanother embodiment, the linking group has the formula Si—Y—Si, wherein Yrepresents a linker that can be null, an amine, ether, linear orbranched C₁-C₁₀ alkyl, or a combination thereof. In one embodiment, Y isselected from O, CH₂, OCH₂CH₂O and O(CH₂CH₂O)_(n), wherein n is aninteger between 1 and 5, between 1 and 10, between 1 and 15, between 1and 20, between 1 and 25, or between 1 and 30.

In another embodiment, the linking group includes one or morephosphorester bonds and/or one or more phosphoramide bonds wherein oneor more phosphorester and/or one or more phosphoramide bonds form acovalent bond with at least one photoreactive group, such that thelinking group includes at least two photoreactive groups. In oneembodiment, the linking group is covalently attached to threephotoreactive groups, wherein each photoreactive group is covalentlybonded to the linking group by a phosphorester or phosphoramide bond. Inanother embodiment, the linking group includes at least one phosphorusatom with a phosphorus-oxygen double bond (P═O), wherein at least onephotoreactive group is bonded to at least one phosphorus atom. In yetanother embodiment, the linking group includes one phosphorus atom witha phosphorus-oxygen double bond (P═O), wherein at least two or threephotoreactive groups are covalently bonded to the phosphorus atom. Inanother embodiment, the linking group includes at least two phosphorusatoms, wherein at least one phosphorus atom includes a phosphorus-oxygendouble bond (P═O), and at least one or at least two photoreactive groupsare covalently bonded to each phosphorus atom.

The linking agent includes one or more photoreactive groups and alinking group, wherein each photoreactive group is independentlyattached to the linking group by a linkage. In other embodiments, thelinking agent includes two or more photoreactive groups. In still otherembodiments, the linking agent includes three or more photoreactivegroups.

The linking agent includes one or more photoreactive groups attached toa linking group. The linking agent can be represented by the formulaPhoto¹-LG-Photo², wherein Photo¹ and Photo² independently represent atleast one photoreactive group and LG represents a linking group. Theterm “linking group” as used herein, refers to a segment or group ofmolecules configured to connect two or more molecule to each another,wherein the linking group is capable of degrading under one or moreconditions. In one embodiment, the linking group includes at least onesilicon atom. In another embodiment, the linking group includes at leastone phosphorus atom.

The term “linking group” as used herein, refers to a moiety configuredto connect one molecule to another, wherein the linking group is capableof cleavage under one or more conditions. The term “biodegradable” asused herein, refers to degradation in a biological system, and includesfor example, enzymatic degradation or hydrolysis. It should be notedthat the term “degradable” as used herein includes both enzymatic andnon-enzymatic (or chemical) degradation. It is also understood thathydrolysis can occur in the presence of or without an acid or base. Inone embodiment, the linking agent is water soluble. In anotherembodiment, the linking agent is not water soluble.

In addition to providing a bond, the linking group can function as aspacer, for example, to increase the distance between the photoreactivegroups of the linking agent. For example, in some instances it may bedesirable to provide a spacer to reduce steric hindrance that may resultbetween the photoreactive groups, which could interfere with the abilityof the photoreactive groups to form covalent bonds with a supportsurface, or from serving as a photoinitiator for polymerization. Asdescribed herein, it is possible to vary the distance between thephotoreactive groups, for example, by increasing or decreasing thespacing between one or more photoreactive groups.

As described herein, one or more photoreactive groups can be bonded to alinking group by a linkage. In one embodiment, the linkage between thephotoreactive group and the linking group includes at least oneheteroatom, including, but not limited to oxygen, nitrogen, selenium,sulfur or a combination thereof. In one embodiment, a photoreactivegroup, linking group and heteroatom form an ether (R¹—O—R²), wherein R¹is a photoreactive group and R² is a linking group. In anotherembodiment, a photoreactive group, linking group and heteroatom form anamine,

wherein R¹ is a photoreactive group, R² is a linking group, and R³ ishydrogen, aryl or alkyl, a photoreactive group, or a hydroxyl or saltthereof. In one embodiment, R³ is cyclic, linear or branched, saturatedor unsaturated, aromatic or heteroaromatic, or a combination thereof.The stability of the ether and/or amine linkage can be influenceddepending upon the size (e.g., chain length, branching, bulk, etc.) ofthe substituents. For example, bulkier substituents will generallyresult in a more stable linkage (i.e., a linking agent that is slower todegrade in the presence of water and/or acid).

In one embodiment, the linking group includes one or more silicon atoms.In a particular embodiment, the linking group includes one silicon atom(which can be referred to as a monosilane) covalently bonded to at leasttwo photoreactive groups. In another embodiment, the linking groupincludes at least two silicon atoms (which can be referred to as adisilane). In one embodiment, the linking group can be represented bythe formula Si—Y—Si, wherein Y represents a linker that can be null(e.g., the linking group includes a direct Si—Si bond), an amine, ether,linear or branched C₁-C₁₀ alkyl, or a combination thereof. In oneembodiment, Y is selected from O, CH₂, OCH₂CH₂O, O(CH(CH3)CH₂O)_(n), andO(CH₂CH₂O)_(n), wherein n is an integer between 1 and 5, between 1 and10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1and 30. One embodiment of a disilane linking agent is shown below

wherein R¹, R², R⁸ and R⁹ can be any substitution, including, but notlimited to H, alkyl, halide, hydroxyl, amine, or a combination thereof;R³, R⁴, R⁶ and R⁷ can be alkyl, aryl or a combination thereof; R⁵ can beany substitution, including but not limited to O, alkyl or a combinationthereof; and each X, independently, can be O, N, Se, S, or alkyl, or acombination thereof. One specific embodiment is shown below:

In one embodiment, the linking agent can be represented by the formula

wherein Photo¹ and Photo², independently, represent one or morephotoreactive groups and n is an integer between 1 and 10, wherein thelinking agent comprises a covalent linkage between at least onephotoreactive group and the linking group, wherein the covalent linkagebetween at least one photoreactive group and the linking group isinterrupted by at least one heteroatom. In general, a longer hydrocarbonchain between the two silicon atoms will tend to increase theflexibility of the linking agent and may facilitate crosslinking betweena greater number of polymers than a linking agent with a shorter carbonchain, since the photoreactive groups can react with polymers locatedfarther apart from one another. In the formula shown above, R¹, R², R³,R⁴ are independently alkyl or aryl, including, but not limited tocyclic, linear or branched, saturated or unsaturated, aromatic orheteroaromatic, or a combination thereof. In a more particularembodiment, R¹-R⁴ are independently phenyl, methyl, ethyl, isopropyl,t-butyl, or a combination thereof. In another embodiment, R¹-R⁴ can alsobe, independently, a photoreactive group. In yet another embodiment,R¹-R⁴ can also be, independently, hydroxyl or salt thereof. In oneembodiment, the hydroxyl salt includes a counterion that is lithium,sodium, potassium, or a combination thereof.

In another embodiment, the linking agent can be represented by theformula

wherein Photo¹ and Photo², independently, represent one or morephotoreactive group, wherein the linking agent comprises a covalentlinkage between at least one photoreactive group and the linking group,wherein the covalent linkage between at least one photoreactive groupand the linking group is interrupted by at least one heteroatom; R¹ andR² are independently alkyl or aryl, including, but not limited tocyclic, linear or branched, saturated or unsaturated, aromatic orheteroaromatic, or a combination thereof. In a more particularembodiment, R¹ and R² are independently phenyl, methyl, ethyl,isopropyl, t-butyl, or a combination thereof. R¹ and R² can also be,independently, a photoreactive group, wherein the linking agentcomprises a covalent linkage between at least one photoreactive groupand the linking group, wherein the covalent linkage between at least onephotoreactive group and the linking group is interrupted by at least oneheteroatom; or hydroxyl or salt thereof. In one embodiment, the hydroxylsalt includes a counterion that is lithium, sodium, potassium, or acombination thereof. One embodiment of a monosilane linking agent isshown below

in which R¹ and R⁵ can be any substitution, including, but not limitedto H, halogen, amine, hydroxyl, alkyl, or a combination thereof; R² andR⁴ can be any substitution, except OH, including, but not limited to H,alkyl or a combination thereof; R³ can be alkyl, aryl or a combinationthereof; and X, independently, can be O, N, Se, S, alkyl or acombination thereof.

In another embodiment, the linking group includes one or morephosphorous atoms. In one embodiment, the linking group includes onephosphorus atom (which can also be referred to as a mono-phosphoruslinking group). In another embodiment, the linking agent includes twophosphorus atoms (which can also be referred to as a bis-phosphoruslinking group). In one embodiment, the linking group comprises at leastone phosphorus atom with a phosphorus-oxygen double bond (P═O), whereinat least one or two photoreactive groups are bonded to the phosphorusatom. In another embodiment, the linking group comprises one phosphorusatom with a phosphorus-oxygen double bond (P═O), wherein two or threephotoreactive groups are covalently bonded to the phosphorus atom. Inanother embodiment, the linking group comprises at least two phosphorusatoms, wherein at least one phosphorus atom includes a phosphorus-oxygendouble bond (P═O), and at least one or two photoreactive groups arecovalently bonded to each phosphorus atom.

In a more particular embodiment, the linking agent can be represented bythe formula:

wherein Photo¹ and Photo², independently, represent one or morephotoreactive groups, wherein the linking agent comprises a covalentlinkage between at least one photoreactive group and the linking group,wherein the covalent linkage between at least one photoreactive groupand the linking group is interrupted by at least one heteroatom and R isalkyl or aryl, a photoreactive group, hydroxyl or salt thereof, or acombination thereof. In one embodiment, the hydroxyl salt includes acounterion that is lithium, sodium, potassium, or a combination thereof.In a more particular embodiment, R is cyclic, linear or branched,saturated or unsaturated, aromatic or heteroaromatic, or a combinationthereof. In a more particular embodiment, R is phenyl, methyl, ethyl,isopropyl, t-butyl, or a combination thereof.

In another embodiment, the linking agent can be represented by formula:

wherein Photo¹ and Photo² independently, represent one or morephotoreactive groups, wherein the linking agent comprises a covalentlinkage between at least one photoreactive group and the linking group,wherein the covalent linkage between at least one photoreactive groupand the linking group is interrupted by at least one heteroatom and R isalkyl or aryl, a photoreactive group (wherein the covalent linkagebetween the photoreactive group and the linking group may be interruptedby at least one heteroatom), hydroxyl or salt thereof, or a combinationthereof. In one embodiment, the hydroxyl salt includes a counterion thatis lithium, sodium, potassium, or a combination thereof. In a moreparticular embodiment, R is cyclic, linear or branched, saturated orunsaturated, aromatic or heteroaromatic, or a combination thereof. Inone embodiment, R is phenyl, methyl, ethyl, isopropyl, t-butyl, or acombination thereof.

In another embodiment, the linking agent can be represented by theformula:

wherein Photo¹ and Photo², independently, represent one or morephotoreactive groups, wherein the linking agent comprises a covalentlinkage between at least one photoreactive group and the linking group,wherein the covalent linkage between at least one photoreactive groupand the linking group is interrupted by at least one heteroatom; Yrepresents a linker that can be N or O (e.g., pyrophosphate), linear orbranched C₁-C₁₀ alkyl, or a combination thereof; and R¹ and R² areindependently alkyl, aryl, a photoreactive group (wherein the covalentlinkage between the photoreactive group and the linking group can beinterrupted by at least one heteroatom), hydroxyl or salt thereof, or acombination thereof. In one embodiment, Y is selected from O, CH₂,OCH₂CH₂O, O(CH(CH3)CH₂O)_(n), and O(CH₂CH₂O)_(n), wherein n is aninteger between 1 and 5, between 1 and 10, between 1 and 15, between 1and 20, between 1 and 25, or between 1 and 30. In one embodiment, thehydroxyl salt counterion is lithium, sodium, potassium, or a combinationthereof. In a more particular embodiment, R¹ and R² are independently,cyclic, linear or branched hydrocarbon, saturated or unsaturated,aromatic or heteroaromatic, or a combination thereof. In one embodiment,R¹ and R² are independently phenyl, methyl, ethyl, isopropyl, t-butyl,or a combination thereof. In general, a longer hydrocarbon chain betweenthe two phosphorus atoms will tend to increase the flexibility of thelinking agent and may facilitate crosslinking between a greater numberof polymers than a linking agent with a shorter carbon chain, since thereactive photoreactive groups can react with polymers located fartherapart from one another. In one embodiment, Y can be O, CH₂, OCH₂CH₂O,O(CH₂(CH3)CH₂O)_(n), and O(CH₂CH₂O)_(n) wherein n is an integer between1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1and 25, or between 1 and 30. One embodiment is shown below

in which R¹, R², R⁴ and R⁵ can be any substitution, including but notlimited to H, alkyl, halogen, amine, hydroxyl, or a combination thereof;R³ can be any substitution, including but not limited to O, alkyl, or acombination thereof; R⁶ and R⁷ can be alkyl, aryl or a combinationthereof; and each X can independently be O, N. Se, S, alkyl, or acombination thereof. In one embodiment, the linking agent includes oneor more phosphorester bonds and one or more phosphoramide bonds, and canbe represented by the formula:

wherein X and X² are, independently, O, N, Se, S or alkyl; R¹ and R² areindependently, one or more photoreactive groups, and X³ is O, N, Se, S,alkyl or aryl; R³ is alkyl or aryl, including, but not limited tocyclic, linear or branched, saturated or unsaturated, aromatic orheteroaromatic, or a combination thereof. In a more particularembodiment, R³ is phenyl, methyl, ethyl, isopropyl, t-butyl, or acombination thereof. R³ can also be a photoreactive group or a hydroxylor salt thereof. In one embodiment, the hydroxyl salt counterion islithium, sodium, potassium, or a combination thereof.

In one embodiment, the linking agent comprises a triphosphorester, whichcan be represented by the formula.

wherein R¹ and R² are independently, one or more photoreactive groups,and R³ is alkyl or aryl, including, but not limited to cyclic, linear orbranched, saturated or unsaturated, aromatic or heteroaromatic, or acombination thereof. In a more particular embodiment, R³ is phenyl,methyl, ethyl, isopropyl, t-butyl, or a combination thereof. R³ can alsobe a photoreactive group or a hydroxyl or salt thereof. In oneembodiment, the hydroxyl salt counterion is lithium, sodium, potassium,or a combination thereof.

In another embodiment, the linking agent comprises a triphosphoramide,which can be represented by the formula.

wherein R¹-R⁶ are independently, a photoreactive group, a hydroxyl orsalt thereof, alkyl or aryl, or a combination thereof, wherein at leasttwo of R¹-R⁶ are, independently, a photoreactive group. In oneembodiment, the hydroxyl salt counterion is lithium, sodium, potassium,or a combination thereof. In a more particular embodiment, R¹-R⁶ areindependently cyclic, linear or branched, saturated or unsaturated,aromatic or heteroaromatic, or a combination thereof. In a moreparticular embodiment, R¹-R⁶ are, independently, phenyl, methyl, ethyl,isopropyl, t-butyl, or a combination thereof.

The linking agent can be formed using any suitable reaction pathway. Inone embodiment, the linking agent is formed by reacting a functionalizedlinking element with one or more, typically two or more photoreactivegroups. As used herein, the term “linking element” refers to the linkinggroup component of the linking agent before it is bonded to one or morephotoreactive groups. The term “functionalized linking element” is usedto indicate that the linking element includes one or more reactivefunctional groups. In one embodiment, the linking element includes oneor more halogen functional groups. The term “halogen” refers tofluorine, chlorine, bromine, or iodine functional groups. In anotherembodiment, the linking element includes one or moretrifluoromethanesulfonate (CF₃SO₃—) functional groups.

In one embodiment, the linking element includes one or more siliconatoms. In one embodiment, the linking element includes one or morehalogen substituents, such as fluorine, chlorine, bromine, iodine, andcombinations thereof. In another embodiment, the linking elementincludes at least two halogen substituents. In another embodiment, thelinking element includes one or more trifluoromethanesulfonate(triflate) substituents. In another embodiment, the linking elementincludes at least two triflate substituents. In a more particularembodiment, the linking element includes one silicon atom with at leasttwo halogen or triflate substituents. In another embodiment, the linkingelement includes at least two silicon atoms. In a more particularembodiment, the linking element includes two silicon atoms, wherein eachsilicon atom includes at least one halogen or triflate substituent. Inone embodiment, the linking element can be represented by the formulaSi—Y—Si, wherein Y represents a linker that can be null, an amine,ether, linear or branched C₁-C₁₀ alkyl, or a combination thereof,wherein each silicon atom includes at least one halogen or triflatesubstituent. In one embodiment, Y is selected from O, CH₂, OCH₂CH₂O,O(CH(CH3)CH₂O)_(n), and O(CH₂CH₂O)_(n), wherein n is an integer between1 and 5, between 1 and 10, between 1 and 15, between 1 and 20, between 1and 25, or between 1 and 30.

In one embodiment, the linking element can be represented by the formula

wherein X¹ and X² are independently halogen, such as fluorine, chlorine,bromine, iodine; trifluoromethanesulfonate; or a combination thereof andn is an integer between 1 and 10. R₁-R₄ are independently alkyl or aryl,including, but not limited to cyclic, linear or branched, saturated orunsaturated, aromatic or heteroaromatic, or a combination thereof. In amore particular embodiment, R¹-R⁴ are independently phenyl, methyl,ethyl, isopropyl, t-butyl, or a combination thereof. In anotherembodiment, R¹-R⁴ can also be, independently, halogen. In yet anotherembodiment, R¹-R⁴ can also be, independently, hydroxyl or salt thereof.In one embodiment, the hydroxyl salt includes a counterion that islithium, sodium, potassium, or a combination thereof.

In another embodiment, the linking element can be represented by theformula

wherein X¹ and X² are independently halogen; such as fluorine, chlorine,bromine, and iodine; or trifluoromethanesulfonate; R¹ and R² areindependently alkyl or aryl, including, but not limited to cyclic,linear or branched, saturated or unsaturated, aromatic orheteroaromatic, or a combination thereof. In a more particularembodiment, R¹ and R² are independently phenyl, methyl, ethyl,isopropyl, t-butyl, or a combination thereof. R¹ and R² can also be,independently, halogen, hydroxyl or hydroxyl salt. In one embodiment,the hydroxyl salt includes lithium, sodium, potassium, or a combinationthereof as a counterion.

In another embodiment, the linking element includes one or morephosphorous atoms. In one embodiment, the linking element comprises atleast one phosphorus atom with a phosphorus-oxygen double bond (P═O),wherein at least one halogen or trifluoromethanesulfonate substituent isbonded to at least one phosphorus atom. In another embodiment, thelinking element comprises one phosphorus atom with a phosphorus-oxygendouble bond (P═O), wherein two or three halogen ortrifluoromethanesulfonate substituents are, independently, covalentlybonded to the phosphorus atom. In another embodiment, the linkingelement comprises at least two phosphorus atoms, wherein at least onephosphorus atom includes a phosphorus-oxygen double bond (P═O), and atleast one or two halogen or trifluoromethanesulfonate substituents arecovalently bonded to each phosphorus atom. In a more particularembodiment, the linking element comprises two phosphorus atoms.

In a more particular embodiment, the linking element can be representedby the formula

wherein X¹ and X² are independently halogen; such as fluorine, chlorine,bromine, and iodine; or trifluoromethanesulfonate; and R is alkyl oraryl, halogen, hydroxyl or a hydroxyl salt, or a combination thereof. Inone embodiment, the hydroxyl salt includes a counterion that is lithium,sodium, potassium, or a combination thereof. In a more particularembodiment, R is cyclic, linear or branched, saturated or unsaturated,aromatic or heteroaromatic, or a combination thereof. In a moreparticular embodiment, R is phenyl, methyl, ethyl, isopropyl, t-butyl,or a combination thereof.

In another embodiment, the linking element can be represented byformula:

wherein X¹ and X² are independently halogen, such as fluorine, chlorine,bromine, and iodine; or trifluoromethanesulfonate and R is alkyl oraryl, halogen, trifluoromethanesulfonate, hydroxyl or salt thereof, or acombination thereof. In one embodiment, the hydroxyl salt includes acounterion that is lithium, sodium, potassium, or a combination thereof.In a more particular embodiment, R is cyclic, linear or branched,saturated or unsaturated, aromatic or heteroaromatic, or a combinationthereof. In one embodiment, R¹ and R² are independently phenyl, methyl,ethyl, isopropyl, t-butyl, or a combination thereof.

In another embodiment, the linking element can be represented by theformula:

wherein X¹ and X² are independently halogen, such as fluorine, chlorine,bromine, and iodine; or trifluoromethanesulfonate, Y represents a linkerthat can be null, an amine, an ether, linear or branched C₁-C₁₀ alkyl,or a combination thereof; and R¹ and R² are independently alkyl, aryl,halogen, hydroxyl or salt thereof, or a combination thereof. In oneembodiment, Y is selected from O, CH₂, OCH₂CH₂O, O(CH(CH3)CH₂O)_(n), andO(CH₂CH₂O)_(n), wherein n is an integer between 1 and 5, between 1 and10, between 1 and 15, between 1 and 20, between 1 and 25, or between 1and 30. In one embodiment, the hydroxyl salt counterion is lithium,sodium, potassium, or a combination thereof. In a more particularembodiment, R¹ and R² are independently, cyclic, linear or branchedhydrocarbon, saturated or unsaturated, aromatic or heteroaromatic, or acombination thereof. In one embodiment, R¹ and R² are independentlyphenyl, methyl, ethyl, isopropyl, t-butyl, or a combination thereof.

Water-Soluble, Degradable Linking Agent

A water-soluble, degradable linking agent suitable for use in thepresent polymeric medical device is described in U.S. Patent ApplicationNos. 61/285,345 and 61/358,464, the disclosure of which is incorporatedherein by reference.

Described in this section is a linking agent that includes a coremolecule with one or more charged groups; and one or more photoreactivegroups covalently attached to the core molecule by one or moredegradable linkers. In one embodiment, the linking agent includes anon-polymeric core molecule. In one embodiment, the non-polymeric coremolecule is a hydrocarbon, including a hydrocarbon that is linear,branched, cyclic, or a combination thereof; aromatic, non-aromatic, or acombination thereof; monocyclic, polycyclic, carbocyclic, heterocyclic,or a combination thereof; benzene or a derivative thereof. In oneembodiment, one or more degradable linkers comprise an amide, an ester,a thiocarbamate, or a combination thereof. In one embodiment, one ormore photoreactive group is an aryl ketone, including, for example,acetophenone, benzophenone, anthraquinone, anthrone, anthrone-likeheterocycles, substituted derivatives thereof, or a combination thereof.In one embodiment, one or more charged groups are negatively charged,including, for example, an organic acid selected from sulfuric acid,sulfonic acid, carboxylic acid, phosphoric acid, phosphonic acid, or acombination thereof. In another embodiment, one or more charged groupsare positively charged, for example, a quaternary ammonium salt.

Described herein is a water-soluble, degradable linking agent. Thedegradable linking agent includes one or more photoreactive groups, oneor more charged groups, and one or more degradable linkers configured tooperably attach one or more photoreactive groups to one or morenegatively charged groups. In one embodiment, the linking agent includesa core having one or more charged groups attached directly or indirectlythereto and one or more photoreactive groups attached to thenon-polymeric core by one or more degradable linkers.

The degradable linking agent includes one or more photoreactive groupsattached to one or more charged groups by a degradable linker. In a moreparticular embodiment, the degradable linking agent includes a coremolecule to which the charged groups and the photoreactive groups can beindependently attached. In one embodiment, the degradable linking agentincludes a non-polymeric core molecule. The term “degradable linker” asused herein, refers to a segment configured to connect one part of thelinking agent to another, wherein the linker is capable of cleavageunder one or more conditions. The term degradable as used herein alsoencompasses “biodegradable linkers.” The term “biodegradable” as usedherein, refers to degradation in a biological system, and includes forexample, enzymatic degradation or hydrolysis. It should be noted thatthe term “degradable” as used herein includes both enzymatic andnon-enzymatic (or chemical) degradation. In one embodiment, thedegradable linker comprises one or more degradable linkages such as anamide, an ester, a thiocarbamate, or combinations thereof.

In addition to providing a degradable segment, the degradable linker canfunction as a spacer, to increase the distance between one or morephotoreactive groups and the core molecule. For example, in someinstances it may be desirable to provide a spacer to reduce sterichindrance that may result between the core molecule and one or morephotoreactive groups that could interfere with the ability of one ormore photoreactive groups to form covalent bonds with a support surface,or from serving as a photoinitiator for polymerization. As describedherein, it is possible to vary the distance between the photoreactivegroups, for example, by increasing or decreasing the spacing between oneor more photoreactive groups.

A degradable linking agent can be represented by the formula:

wherein X¹ and X² include, independently, one or more photoreactivegroups, for example, an aryl ketone photoreactive group, including, butnot limited to, aryl ketones such as acetophenone, benzophenone,anthraquinone, anthrone, anthrone-like heterocycles, their substitutedderivatives or a combination thereof; D¹ and D² are, independently,degradable segments, including, for example, degradable segments thatinclude an amide, an ester, a thiocarbamate, or a combination thereof; Yrepresents a core molecule, which can be either polymeric ornon-polymeric, including, but not limited to a hydrocarbon, including ahydrocarbon that is linear, branched, cyclic, or a combination thereof;aromatic, non-aromatic, or a combination thereof; monocyclic,polycyclic, carbocyclic, heterocyclic, or a combination thereof; benzeneor a derivative thereof; or a combination thereof; and Z represents oneor more charged groups, including, for example, one or more negativelycharged groups such as an organic acid salt, including but not limitedto sulfuric acid, sulfonic acid, carboxylic acid, phosphoric acid,phosphonic acid, or a combination thereof; one or more positivelycharged groups, for example, a quaternary ammonium salt, or acombination thereof.

In the formula shown above, the two or more photoreactive groups (X¹ andX²) are discrete. As used herein, the term “discrete” means that the twoor more photoreactive groups are distinct from each other, as comparedto a bifunctional photoreactive agent, that can include two or morephotoreactive moieties, such as a conjugated cyclic diketone whereineach ketone group of the diketone is adapted to serve as a photoreactivemoiety capable of being activated in order to provide a free radical. Itis also understood that the first and second photoreactive groups and/orthe first and second degradable linkers may or may not be the same. Forexample, in one embodiment, the photoreactive groups (X¹ and X²) are thesame or identical. In another embodiment, the photoreactive groups (X¹and X²) are not the same. In one embodiment, the degradable linker (D¹and D²) are the same or identical. In another embodiment, the degradablelinker (D¹ and D²) are not the same. In one embodiment, thephotoreactive groups include one or more first photoreactive groupsadapted to attach the linking agent to a surface and one or more secondphotoreactive groups adapted to initiate photopolymerization.

In one embodiment, the degradable linker is a biodegradable linker thatincludes an amide bond (also referred to as a peptide bond, or peptidelinker). A peptide bond can be cleaved by amide hydrolysis (the additionof water) by enzymatic and non-enzymatic reactions. Proteolysis refersto amide hydrolysis catalyzed by an enzyme. The term “protease” refersto an enzyme that conducts proteolysis. Examples of enzymes capable ofhydrolyzing a peptide bond include, but are not limited to, acylase,amidohydrolase, deaminase, trypsin, and alpha-chymotrypsin.

A nonlimiting example of a degradable linker with a peptide bond can berepresented by formula I:

wherein X¹ and X² include, independently, one or more photoreactivegroups, including, but not limited to, aryl ketone photoreactive groups,such as acetophenone, benzophenone, anthraquinone, anthrone,anthrone-like heterocycles, their substituted derivatives or acombination thereof; Y represents a core molecule, which can bepolymeric or non-polymeric, including for example, non-polymericmolecules such as a hydrocarbon, including linear, branched or cyclic;aromatic or non-aromatic; monocyclic, polycyclic, carbocyclic orheterocyclic; benzene or a derivative thereof; or combinations thereof;Z¹ and Z² represent, independently, one or more charged groups,including positively and negatively charged groups, for example anegatively charged group that includes an organic acid salt, includingbut not limited to sulfuric acid, sulfonic acid, carboxylic acid,phosphoric acid, phosphonic acid, or a combination thereof; one or morepositively charged groups, for example, a quaternary ammonium salt; or acombination thereof. R¹, R², R³, and R⁴ are, independently, spacerelements that can be null, a heteroatom, alkyl or aryl, including, butnot limited to cyclic, linear or branched, saturated or unsaturated,aromatic or heteroaromatic, or a combination thereof; R⁵ and R⁶ are,independently, spacer elements that can be null, alkyl or aryl,including, but not limited to cyclic, linear or branched, saturated orunsaturated, aromatic or heteroaromatic, or a combination thereof; andR⁷ and R⁸ are, independently substituents that can be hydrogen, alkyl oraryl, including, but not limited to cyclic, linear or branched,saturated or unsaturated, aromatic or heteroaromatic, or a combinationthereof.

More specific examples of a degradable linker that includes a degradableamide bond include those shown in formulae II and III:

wherein X¹ and X² include, independently, one or more photoreactivegroups, including, but not limited to aryl ketone photoreactive groups,such as acetophenone, benzophenone, anthraquinone, anthrone,anthrone-like heterocycles, their substituted derivatives or acombination thereof; and R¹, R², R³, and R⁴ are, independently, spacerelements, which can be null, alkyl or aryl, including, but not limitedto cyclic, linear or branched, saturated or unsaturated, aromatic orheteroaromatic, or a combination thereof; and R⁵ and R⁶ are,independently substituents that can be hydrogen, alkyl or aryl,including, but not limited to cyclic, linear or branched, saturated orunsaturated, aromatic or heteroaromatic, or a combination thereof.

More specific examples of linkers with degradable peptide bonds areshown in formula IV, below, wherein R¹ and R² are, independently,substituents that can be hydrogen, alkyl or aryl, including, but notlimited to cyclic, linear or branched, saturated or unsaturated,aromatic or heteroaromatic, or a combination thereof; and R³ and R⁴ are,independently, spacer elements, which can be null, alkyl or aryl,including, but not limited to cyclic, linear or branched, saturated orunsaturated, aromatic or heteroaromatic, or a combination thereof.

In another embodiment, the degradable linking agent includes one or moreester bonds. Esters can be hydrolyzed to the parent carboxylic acid andan alcohol under acidic or basic conditions. An example of a linker witha degradable ester bond is shown in formula V and VI.

wherein X¹ and X² include, independently, one or more photoreactivegroups, including but not limited to aryl ketone photoreactive groups,such as acetophenone, benzophenone, anthraquinone, anthrone,anthrone-like heterocycles, their substituted derivatives or acombination thereof; and R¹, R², are, independently, spacer elements,which can be null, alkyl or aryl, including, but not limited to cyclic,linear or branched, saturated or unsaturated, aromatic orheteroaromatic, or a combination thereof. R³ and R⁴ are, independently,spacer elements, which can be null, a heteroatom, including, but notlimited to O, N or S, alkyl or aryl, including, but not limited tocyclic, linear or branched, saturated or unsaturated, aromatic orheteroaromatic, or a combination thereof.

In another embodiment, the degradable linking agent includes one or morethiocarbamate bonds. Thiocarbamates are carbamates in which the C═Ogroup has been replaced by a C═S group. One example of a degradablelinker with a thiocarbamate bond can be represented by formula VII:

wherein X¹ and X² include, independently, one or more photoreactivegroups, including but not limited to aryl ketone photoreactive groups,such as acetophenone, benzophenone, anthraquinone, anthrone,anthrone-like heterocycles, their substituted derivatives or acombination thereof; R¹ and R² are, independently, spacer elements,which can be null, a heteroatom, including, but not limited to O, N orS, alkyl or aryl, including, but not limited to cyclic, linear orbranched, saturated or unsaturated, aromatic or heteroaromatic, or acombination thereof; and R³ and R⁴ are, independently, spacer elements,which can be null, alkyl or aryl, including, but not limited to cyclic,linear or branched, saturated or unsaturated, aromatic orheteroaromatic, or a combination thereof.

In some embodiments, a separate material can be disposed in a layer overthe first material or portion. Referring now to FIG. 8, across-sectional schematic view of a spacing element 800 is shown inaccordance with various embodiments herein. The spacing element 800 caninclude an inner portion 802 including a first material. The innerportion 802 can define a central lumen 804. The spacing element 800 canalso include an outer portion 806 including a second material. The outerportion 806 can be continuous or discontinuous over the surface of thespacing element 800 (for example, the outer portion can havediscontinuities such as pores or openings). The outer portion 806 caninclude a water permeable material. The outer portion 806 can include alubricious coating. In some embodiments the outer portion 806 caninclude a layer of flashspun high-density polyethylene fibers. In someembodiments the outer portion 806 can include a layer of expandedpolytetrafluoroethylene (ePTFE). In some embodiments, the outer portion806 can include a layer of graphene. In some embodiments, the outerportion 806 can include a layer of graphene with a modifying compoundcovalently bonded thereto. For example, a linking agent can becovalently bonded to the graphene and to another compound having desiredfunctional properties thereby providing the graphene surface with thoseproperties.

In some embodiments, the spacing elements can define a volume that canbe filled with another components, can be inflated with air or a liquid,or that can be used to retain absorbed exudate (for example, as a fluidsequestering agent), and/or and antimicrobial agent. In someembodiments, the interior of the spacing elements is hollow. Referringnow to FIG. 9, a cross-sectional schematic view of a spacing element 900in accordance with various embodiments herein is shown. The spacingelement 900 can include an outer layer 922 and an inner layer 924 thatare separate from one another in cross-section such that they define avolume 928. The inner layer 924 can define a central lumen 926. In someembodiments, the outer layer 922 can include a material with elastomericproperties (for example, but not limited to, polyurethane) such that itcan expand in size in response to the volume being filled with a fluid(such as air or a liquid) or other matter (such as a dispersion).

In some embodiments, the spacing element can define a volume that can befilled with a material that aids in absorbing exudate. Referring now toFIG. 10, a cross-sectional schematic view of a spacing element 1000 inaccordance with various embodiments herein is shown. The spacing element1000 can include an outer layer 1022 and an inner layer 1024 that areseparate from one another in cross-section such that they define avolume 1028. The inner layer 1024 can define a central lumen 1026. Inthis embodiment, a plurality of hollow fibers 1030 are disposed withinthe volume 1028. In some embodiments, the hollow fibers can be apolysulfone polymer.

In some embodiments, the spacing elements can include one or moreinterior volumes other than the central lumen. Referring now to FIG. 11a cross-sectional schematic view of a spacing element 1100 is shown inaccordance with various embodiments herein. The spacing element 1100 isshown including a portion 1102 surrounding a central lumen 1104. Thespacing element 1100 can further include a plurality of interior volumes1132 that can be used to store exudate or can be filled with anothermaterial.

In addition, various other elements can be disposed within spacingelements. By way of example, in some embodiments a radio frequencyidentification device (RFID) can be disposed within a spacing element.In some embodiments a metal, such as a ferrous metal, can be disposedwithin a spacing element. In some embodiments a radiopaque material canbe disposed within a spacing element. These exemplary elements, disposedwithin spacing elements, can be useful for detection and/or retrieval ofwound packing devices from wounds.

Referring now to FIG. 12, a cross-sectional schematic view of aconnector 1200 is shown in accordance with various embodiments herein.The connector 1200 can include a wall member 1202. The wall member 1202can define a central lumen 1204. However, in other embodiments, theconnector 1200 is solid in cross-sectional. In some embodiments, amaterial can be disposed within the lumen of the connector.

Referring now to FIG. 13, a cross-sectional schematic view of aconnector 1300 in accordance with various embodiments herein. Theconnector 1300 can include a wall member 1302 defining a central lumen1304. A material 1334 can be disposed within the lumen 1304. By way ofexample, the material 1334 can include absorbent materials. In someembodiments the material 1334 can include superabsorbent materials. Insome embodiments, calcium chloride can be disposed within the lumen1304.

In some embodiments, the connector can be in fluid communication withone or more of the spacing elements such that fluid from one or morespacing elements can be transferred to the connector. In someembodiments the lumen of the connector is accessible from an end of theconnector providing fluid communication between one or more of thespacing elements and the end of the connector. Exemplary fluidcommunication can provide for a negative pressure, or a suction, toremove exudate from the wound. Additionally, the wound can be covered,for example, with an adhesive film, such as a transparent dressing(TEGADERM Dressing, available from 3M Company, St. Paul, Minn.) toimpart negative pressure over the entire aspect of the wound, and notjust on the wound exudate.

Other embodiments can include applying a gas-impermeable wound dressingbarrier over the wound and wound packing device. The method can furtherinclude regulating the negative pressure applied to the wound bed viathe connector(s) and/or spacer(s) and for the degree of exudate removalachieved. The magnitude of negative pressure applied can also be furtheroptimized for a particular tissue response and wound healing.

In yet other embodiments, the method can include putting a wounddressing that is a gas-permeable sterile barrier over the wound andpreviously placed wound packing device. The method can further includeregulating the magnitude of vacuum or negative pressure applied to theconnector(s) and spacer(s). In this example, the resulting pressurethroughout the wound bed will be essentially atmospheric pressure orslightly less, and the degree of exudate removal may be independentlycontrolled and optimized.

In some embodiments, the connector can include a core and a layer of amaterial disposed over the core. Referring now to FIG. 14, across-sectional schematic view is shown of a connector 1400 inaccordance with various embodiments herein. The connector 1400 caninclude a core 1436 and a layer 1402 disposed over the core 1436. Insome embodiments, layer 1402 is a porous sleeve. In some embodimentslayer 1402 can include a lubricious coating. In some embodiments layer1402 can include a layer of flashspun high-density polyethylene fibers.In some embodiments layer 1402 can include a layer ofpolytetrafluoroethylene (PTFE).

It will be appreciated that spacing elements in accordance withembodiments herein can take on various shapes and sizes. By way ofexample, the spacing elements can be spherical, ovoid, toroidal, cubic,or the like. Referring now to FIG. 15, a schematic view is shown of aspacing element 1502 in accordance with various embodiments herein. Thespacing element is shown attached to a connector 1504. Referring now toFIG. 16, a schematic view is shown of a spacing element 1602 inaccordance with various embodiments herein. In this view, the spacingelement 1602 is shown attached to a connector 1604.

Referring now to FIG. 17, a schematic view is shown of a connector 1704and spacing element 1702 in accordance with various embodiments herein.The spacing element can include an aperture 1738. An end portion 1740 ofthe connector 1704 can fit within the aperture 1738 of an adjacentspacing element. In some embodiments, the end portion of a connectorsegment can be retained within the aperture of an adjacent spacingelement. By way of example, a friction-fit retention mechanism can beused to retain the end portion of the connector segment within theaperture. In this manner, multiple connector segment and spacing elementpairs can be attached together to form a wound packing device.

Referring now to FIG. 18, a schematic view is shown of connectorsegments and spacing elements attached to one another to form a woundpacking device 1800 in accordance with various embodiments herein. Thisembodiment can allow for customization of size of the wound packingdevice 1800. In specific, a first connector segment and spacing elementpair 1802 is attached to a second connector segment and spacing elementpair 1804, which it turn is attached to another connector segment andspacing element pair 1806. In actual use, any desired number ofconnector segment and spacing element pairs can be attached together.For example, in some embodiments from three to sixty pairs can beattached together.

In some embodiments, indicia can be disposed on portions of the woundpacking device. By way of example, indicia, such as specific coloration,letters, numbers, embossed surface characterizations, or combinationsthereof can be disposed on spacing elements. Such indicia can be usefulfor various purposes. The indicia can allow an end user to more easilytrack the number of spacing elements being used, or to more quicklyidentify a default number of spacing elements by sight and/or feel. Forexample, every 10^(th) spacing element can be a different color in someembodiments. In some embodiments, a material can be used to form coloron the spacing element that will change with time so as to indicate to auser when the device should be exchanged for a new device. In someembodiments, the color is configured to change with time. In someembodiments, the color is configured to change with the amount ofexudate absorbed. Referring now to FIG. 19, a schematic view is shown ofa wound packing device 1900 in accordance with various embodimentsherein. The wound packing device 1900 includes a plurality of spacingelements 1902 attached together with a connector 1904. The wound packingdevice 1900 can also include a first colored spacing element 1940 and asecond colored spacing element 1942. In some embodiments, the firstcolored spacing element 1940, second colored spacing element 1942, andother spacing elements 1902 are all different colors. In someembodiments, the first colored spacing element 1940 and the secondcolored spacing element 1942 are the same color. In yet otherembodiments the first colored spacing element 1940 and second coloredspacing element 1942 can have an embossed surface, whereas other spacingelements 1902 can have a smooth surface.

In some embodiments, spacing elements can be disposed together within acontainer, such as a bag, to form a wound packing device. Referring nowto FIG. 20, a schematic view is shown of wound packing device 2000including a plurality of spacing elements 2002 disposed within acontainer 2044. In some embodiments the container 2044 can be a waterpermeable bag. The container can enclose a space 2046 and the spacingelements 2002 can be within the space 2046. In some embodiments, thespacing elements 2002 can be attached to one another with a connector.In other embodiments, the connector can be absent.

In some embodiments, other materials can be packed along with thespacing elements and/or connector. By way of example, in someembodiments, the spacing elements can be packed with a paste inside of abag or container. In some embodiments, the spacing elements are removedfrom the container before insertion into a wound bed, in otherembodiments the spacing elements stay in the container and thecombination is inserted into the wound bed. Referring now to FIG. 21, aschematic view is shown of a wound packing device 2100 includingplurality of spacing elements 2102 disposed with a packing material 2150inside of a container 2148. In some embodiments, the container 2148 caninclude an egress neck 2152 which can be opened to form an orificethrough which the materials can be dispensed out of the container 2148and into a wound bed. In yet other embodiments the egress neck 2152 canbe an extended cannula through which the wound packing device 2100 canbe delivered into a deep wound or fistula.

As previously described, various embodiments here include nanotexturedsurfaces. Referring now to FIG. 22, a schematic cross-sectional view isshown of a portion 2200 of a device in accordance with variousembodiments herein. The portion 2200 of the device shown can include asurface 2202 that is nanotextured. The portion 2200 shown can include acore portion of material 2204 (or substrate) that can be effective toabsorb exudate. In other embodiments, the core portion of material 2204may be made from a material that does not absorb exudate. In someembodiments, the core portion of material 2204 is swellable. In someembodiments, the core portion of material 2204 is non-swellable. In someembodiments, core portion of material 2204 can be comprised of a porousmaterial. In some embodiments, the core portion of material 2204 can becomprised of a non-porous material. In some embodiments, core portion ofmaterial 2204 includes a fluid sequestering material. In someembodiments, core portion of material 2204 forms part of a spacingelement.

Referring now to FIG. 23 is a schematic cross-sectional view of aspacing element 2300 in accordance with various embodiments herein. Thespacing element 2300 can include a nanotextured surface 2302 and a coreportion of material 2304. The spacing element 2300 can define a centralchannel or lumen 2306. The connector (not shown in this view) can passthrough the lumen 2306.

FIG. 24 is a schematic view of a wound packing device 2400 in accordancewith various embodiments of the invention. The wound packing device 2400includes a plurality of spacing elements 2402 attached together with aconnector 2404. The surface of the spacing elements 2402 can benanotextured.

In some embodiments, wound packing kits are included. By way of example,kits can include a plurality of spacing elements, the spacing elementscomprising a nanotextured surface, the plurality of spacing elementsconfigured to absorb exudate. The kits can also include a connector forconnecting the plurality of spacing elements to one another. Theconnector comprising a fitting to allow for the number of spacingelements connected to one another by the connector to be modified by anend user.

Methods

In some embodiments, a method of making a wound packing device isincluded. The method can include forming a plurality of spacingelements. It will be appreciated that are many different techniques thatcan be used to form spacing elements in accordance with embodimentsherein. In some embodiments, the spacing elements can be molded,sprayed, dipped, and the like. In some cases, depending on the polymersused, the composition will also include a solvent. In other embodiments,the composition can be solventless before forming into a spacingelement. In some embodiments, manufacturing can include a number ofsteps. For example, the inner region or core of the spacing element canbe formed in a first operation and then a layer of material can bedisposed on top of the inner region. The method can also include anoperation of mounting a plurality of spacing elements on a connector.Mounting can include forming the spacing elements in place on theconnector. Mounting can also include threading the spacing elements ontothe connector. In some embodiments, an adhesive can be used to retainthe spacing elements in place on the connector. In other embodiments,spacing elements can be retained in place through a friction fit. Insome embodiments, the method can include an operation of inflating thespacing elements.

In some embodiments, a method of treating wounds is included. The methodcan include dispensing a wound packing device from a sterile package. Insome embodiments, dispensing can include removing a portion of spacingelements from a multi-segment package, such that other portions remainunopened and sterile. In some embodiments, dispensing can includecounting the number of spacing elements. In some embodiments dispensingcan include cutting the connector, or otherwise separating a portion ofthe connector, in order to prepare a desired number of spacing elementsfor insertion into a wound bed. The method can further include insertingthe wound packing device into a wound bed. In some embodiments, themethod can further include putting a wound dressing over the woundpacking device. In some embodiments, the method can also includeattaching a vacuum system (or another device that can generate anegative air pressure) to the wound packing device. By way of example, avacuum system can be put in fluid communication with the connector,which can transfer exudate away from the spacing devices.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

It should also be noted that, as used in this specification and theappended claims, the phrase “configured” describes a system, apparatus,or other structure that is constructed or configured to perform aparticular task or adopt a particular configuration to. The phrase“configured” can be used interchangeably with other similar phrases suchas arranged and configured, constructed and arranged, constructed,manufactured and arranged, and the like.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A wound packing device comprising: a plurality of spacing elements,the spacing elements comprising a nanotextured surface; a connectorconnecting the plurality of spacing elements to one another; and whereinthe plurality of spacing elements are capable of absorbing exudate. 2.The wound packing device of claim 1, the surface of the spacing elementsexhibiting antimicrobial activity.
 3. The wound packing device of claim1, the surface of the spacing elements comprising at least one of silverions, quaternary amines, or tobramycin. 4-5. (canceled)
 6. The woundpacking device of claim 1, comprising from 4 to 50 spacing elements.7-16. (canceled)
 17. The wound packing device of claim 1, each spacingelement capable of absorbing an amount of exudate equal to at least theweight of the spacing element. 18-22. (canceled)
 23. The wound packingdevice of claim 1, the spacing elements comprising a core and an outerlayer disposed on the outside surface of the core, the outer layercomprising a water permeable material.
 24. The wound packing device ofclaim 1, the spacing element comprising a plurality of pores.
 25. Thewound packing device of claim 1, the spacing element comprising a fluidsequestering agent. 26-44. (canceled)
 45. The wound packing device ofclaim 1, further comprising a lubricious coating disposed on the spacingelements.
 46. The wound packing device of claim 1, further comprising alubricious coating disposed on the connector. 47-48. (canceled)
 49. Thewound packing device of claim 1, further comprising a layer of graphenedisposed over the spacing elements.
 50. The wound packing device ofclaim 1, further comprising a layer of graphene disposed over thespacing elements, further comprising a modifying agent covalently bondedto the graphene. 51-63. (canceled)
 64. The wound packing device of claim1, wherein the spacing elements are colored, including at least twodifferent colors amongst the beads.
 65. The wound packing device ofclaim 64, wherein the color of the spacing elements changes according tothe amount of exudate absorbed.
 66. (canceled)
 67. The wound packingdevice of claim 1, further comprising a modifying agent covalentlybonded to the surface of the spacing elements.
 68. The wound packingdevice of claim 1, further comprising a radiopaque material.
 69. Thewound packing device of claim 1, the nanotextured surface comprising ananometer scale surface geometry sufficient to inhibit adherence ofbacterial cells to the nanotextured surface.
 70. The wound packingdevice of claim 1, the nanotextured surface comprising a nanometer scalesurface geometry sufficient to inhibit adherence of bacterial cells tothe nanotextured surface.
 71. A wound packing device comprising: aplurality of spacing elements, the spacing elements comprising ananotextured surface; and a container, the plurality of spacing elementdisposed within the container. 72-73. (canceled)
 74. A method of makinga wound packing device comprising: forming a plurality of spacingelements, the spacing elements comprising a nanotextured surface; andmounting a plurality of spacing elements on a connector. 75-80.(canceled)